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Small-cell lung cancer (SCLC) responds poorly to immune checkpoint blockade, but how tumor-cell states shape the myeloid microenvironment remains unclear. Here we identify downstream neighbor of SON (DONSON) as a prognostic factor associated with macrophage-related programmes in SCLC. Across bulk transcriptomic cohorts, clinical specimens, and mouse and human single-cell atlases, DONSON is preferentially expressed in malignant epithelial cells and is associated with neuroendocrine features and an immunosuppressive phenotype. Genetic perturbation of DONSON alters SCLC-cell proliferation, apoptosis and tumor growth, as well as macrophage migration and M2-like polarization. DONSON abundance also tracks with p38 MAPK activity and macrophage migration inhibitory factor (MIF) expression and secretion. Pharmacological inhibition, constitutively active MKK6 rescue, and MIF gain- and loss-of-function experiments support functional contributions of p38 and MIF to these phenotypes. Regorafenib alters the thermal stability of endogenous DONSON and enhances anti-PD-1 activity in syngeneic SCLC models, accompanied by increased proportions of CD86-positive macrophages and IFN-γ-positive CD8⁺ T cells. These findings implicate a DONSON-associated p38-MIF programme in neuroendocrine SCLC and tumor-macrophage crosstalk, nominating this pathway for further therapeutic investigation.